This Phase IIB SBIR finalizes development, conducts in depth preclinical testing, and completes Verification and Validation of the Portable Transdermal Acoustic Patch (TAP) for Delivery of Large Molecules to Improve HIV Patient Medication Regime Compliance by Elimination of Side-Effects, Including Injection Site Reactions. Nearly 37 million people worldwide are living with HIV, with roughly 2.4 million in North America and Western and Central Europe. The main treatment approach for HIV is Highly Active Antiretroviral Therapy, which uses multiple medications to arrest viral replication. HIV medication regimens must be taken with near perfect compliance to maximize benefits and prevent the development of viral resistance. If the HIV virus becomes resistant to treatment, salvage drugs, such as the fusion inhibitor T-20, must be tried. While T- 20 is very effective, a major side-effect - additional to injection pain - is an injection site reaction (ISR), which is experienced by 98% of patients and reduced the rate of adherence (95% of prescribed doses) of patients in one clinical study to 58%, despite the risks of poor compliance. A method to deliver antiretrovirals without adverse side effects is needed, as well as a low-cost, simple delivery approach usable in developing nations. TAP uses ~20 kHz ultrasonic waves to gently open micro-channels in the skin's stratum corneum, enabling large molecule (> 500 Da) medications like T-20 to reach the blood system. TAP is designed to operate at low acoustic intensity levels (100mW/cm2) that do not cause significant skin changes. TAP is a platform technology that delivers large molecule drugs such as broadly neutralizing antibodies, novel entry inhibitors, and T-20 without the ISR - leading to greater patient compliance and positive therapeutic clinical outcomes. The Phase II project met the Specific Aims, demonstrating that T-20 could be delivered at clinically comparable doses, without causing skin damage, in a 30 day porcine study (N=31). The Phase IIB will determine the dose linearity of T-20 delivered transdermally, and demonstrate delivery of a clinical dose (? 2.0g/mL) of T-20 at three differet anatomical regions (skin thicknesses) in an in vivo porcine model. Phase IIB Specific Aims: Aim 1 TAP design and T-20 activity verified (Months 1-12). Acceptance Criteria: T-20 maintains HIV antiviral activity in vitro after 30-min ultrasound application (p<0.05). 60/60 (where applicable) Active Patches and 10/10 Control Boxes pass Verification tests: a) Performance, b) Safety (including IEC), c) Shipping vibration, and d) Reliability and Lifetime. 15/15 Subjects pass Usability. Aim 2 Optimized dosing and treatment achieve clinical T-20 plasma levels (Months 8-14). Acceptance Criteria: TAP (Beta-II) treatment duration and T-20 dosage determined that produce T-20 Ctrough levels of at least 2.0 g/mL in porcine model after one week of treatment. Aim 3 Porcine skin study towards FDA Investigational Device Exemption (Months 15-24). Acceptance Criteria. Demonstrate sufficient T-20 bioavailability (Ctrough ? 2.0 g/mL) is achieved with optimal treatment parameters for porcine skin in vivo at 3 different anatomical regions.